The Role of Probiotics in Cancer Treatment: Emphasis on their In Vivo and In Vitro Anti-metastatic Effects

Probiotics are defined as live bacteria and yeasts that exert beneficial effects for health. Among their various effects, anti-cancer properties have been highlighted in recent years. Such effects include suppression of the growth of microbiota implicated in the production of mutagens and carcinogens, alteration in carcinogen metabolism and protection of DNA from oxidative damage as well as regulation of immune system. We performed a computerized search of the MEDLINE/PUBMED databases with key words: cancer, probiotics, lactobacilli, metastasis and invasion. Cell line studies as well as animal models and human studies have shown the therapeutic effects of probiotics in reduction of invasion and metastasis in cancer cells. These results support the beneficial effects of probiotics both in vitro and in vivo. However, pre-clinical or clinical studies are not enough to decide about their application.

The schematic description of various molecules and cells involved in the metastasis. Metastasis cascade include loss of cell-cell adhesion, acquisition of the ability to interrupt the basement membrane, invasion into the stroma (local invasion), passing the blood circulation (intravasation), staying alive in the circulation before they can reach to a remote organ, extravasation and production of clinically evident metastases. Several molecules are involved in each step. TAM: tissue activated macrophage; CSC: cancer stem cell; BMDC: bone marrow derived cells change expression of different genes participating in cell death and apoptosis (3), invasion and metastasis (4), cancer stem cell maintenance (5) as well as cell cycle control (6). Further studies have shown their modulatory effects on the cancerrelated signaling pathways in a cell type specific manner (7)(8)(9). In addition, their anti-proliferative effects have been assessed in several cell line studies (10)(11)(12). Notably, a traditional fermented milk product has been shown to inhibit in vitro proliferation of MCF-7 breast cancer cells but not normal mammary epithelial cells which implies that the bioactive substances prompt responses that are specifically detected in tumor cells (13). Special attention has been given to the effects of probiotics in reduction of invasion and metastasis in cancer cells in cell line studies as well as animal models and human studies. Invasion and metastasis have been regarded as important hallmarks of malignant cells which are endowed to them through diverse and complex genetic or epigenetic aberrations as well as extrinsic signals, such as those relayed from their microenvironment (14). The schematic description of various molecules and cells involved in metastasis are summarized in Figure 1.
Metastasis cascade include acquisition of the ability to interrupt the basement membrane, invasion into the stroma (local invasion), passing the blood circulation (intravasation), staying alive in the circulation before they can reach to a remote organ, and production of clinically evident metastases.
During this process, cancer cells recruit numerous stromal cells to support them in each step.
Consequently, cancer microenvironment not only participates in the early steps of carcinogenesis but also contributes in metastasis cascade (15). Several

Evidence acquisition
We performed a computerized search of the MEDLINE/PUBMED, Web of Knowledge, Scopus, ProQuest and Google Scholar databases with key words: cancer, probiotics, lactobacilli, metastasis, and invasion within the maximal date range until 2017.

Cell-cell adhesion
Tight junction between epithelial and endothelial cells has a critical role in preserving cell to cell integrity. Defects in this structure underlie the invasion and thus metastasis process (16 (18).
Such decrease in cell invasion has been later found to be accompanied by a decrease in matrix metalloproteinase-9 (MMP-9) protein level in cultured metastatic human colorectal carcinoma cells and an increase in the level of the tight junction protein ZO-1 in cultured metastatic human colorectal carcinoma cells (19). In addition, perioperative probiotic treatment has been shown to maintain the liver barrier in patients undergoing colorectal liver metastases surgery (20). A more recent study has shown that L. rhamnosus and L. Invasion inhibition effect of L. acidophilus was more than that of L. casei (38). As targeting tumor cell motility within the primary tumor is capable of prevention local invasion (39), colonization of lactobacilli in the site of the primary tumor may be beneficial in the prevention of metastases.

Epithelial-mesenchymal transition (EMT)
EMT is a biological process that permits a substances (19). Additional studies for the identification of the bioactive components and their mechanism of action could lead to the application of probiotics as a nutritional modality to prevent metastasis.

Conflict of interest
Authors declare no conflict of interest.